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Smuggling RNA into cells can activate the immune system to fight cancer

Training the body’s immune cells to seek out and fight cancer is a promising new approach in the fight against the disease. That’s because immune cells are already generally equipped to distinguish between healthy and infected or diseased cells. But in many cases, the cancers themselves have evolved ways to either dampen or evade the normal immune response.

The idea of a “cancer vaccine” to amp up the immune system to overcome these tactics is appealing but difficult to implement. But recently immunologist and oncologist Ronald Levy, MD, joined forces with chemists Paul Wender, PhD, and Robert Waymouth, PhD, to learn whether introducing bits of genetic code called mRNAs into a special class of immune cells could do the trick.

The researchers published their results last week in the Proceedings of the National Academies of Science.

Typically, researchers wishing to activate an immune response — whether it be for a standard run-of-the-mill vaccination or even cancer immunotherapy — focus on delivering a protein specific to the virus or cell to which they want to trigger an attack. The immune system recognizes the foreign protein and ramps up its response to the perceived threat. In contrast, mRNA molecules provide protein-making instructions to a cell, rather than the protein itself. This approach has one main advantage.

As Wender explained to me in a recent email:

mRNAs can be used to code for the synthesis of almost any protein and that message can be catalytically expressed, or used repeatedly, by a cell to make many copies of the protein.

That is, once in a cell one mRNA molecule can trigger the production of multiple copies of a given protein, intensifying and prolonging the immune response.

The type of cell the researchers targeted in their study is called an antigen-presenting cell, or APC. APCs serve as a kind of bulletin board in an old West post office, displaying cancer proteins like “wanted” posters. Passing immune cells then take note and ready themselves to attack and kill the rogue cancer cells throughout the body. Wender, Levy and Waymouth wondered whether they could introduce mRNAs into the antigen-presenting cells that encoded cancer-specific proteins, or antigens, of their choice.

The concept is easier explained than done, however. As my colleague Taylor Kubota elegantly explained in earlier news coverage, mRNAs are negatively charged, while the cell membrane is positively charged. This makes it extremely difficult to transport mRNA molecules through the cell membrane and into the cell.

Waymouth and Wender came up with a transport system they’ve termed CART (for charge-altering releasable transporters) that enfolds the mRNA and ferries it across the membrane. Once inside, the transporters naturally degrade into neutral small molecules, releasing the mRNA to be recognized and translated by the cell’s protein-making machinery.

In the current study, the researchers used the CART system to teach immune cells in mice to recognize and destroy lymphoma cells throughout the animals’ bodies. The approach was uncommonly successful: Eight of ten mice with moderately sized tumors experienced a complete regression of measurable tumors, and 40 percent of mice with larger tumors were cured of their disease.

“I was surprised that the CART treatment was able to cure the animals with already established tumors,” Levy said. In the future, the researchers hope to target real tumor antigens and prove that the system is safe for humans.

Wender added:

Obviously, there is more to be done to move this from animal models to human trials, but the current results are very encouraging and bode well for the future. CARTs provide a robust and general solution to ‘delivery’, which is a, if not the, major obstacle associated with the implementation of many emerging technologies.